Generation of an In Vivo Senescent Cell Atlas: Across the life-course and in pathology
Lead Research Organisation:
Babraham Institute
Department Name: Epigenetics
Abstract
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Technical Summary
Senescence is functionally implicated in a myriad of pathophysiological settings, including ageing, wound healing and tumour development. Whilst there is a general consensus that this is in part mediated through the acquired senescence-associated secretory phenotype (SASP), much of this work has been performed in vitro, across a limited number of cell lines. We currently have a limited understanding of what constitutes senescence in vivo, in these diverse cellular and pathological settings, and whether the functional programmes underlying senescence contain tissue and context specific features. As such we intend to isolate senescent populations from a number of distinct pathophysiological states using two fluorescent reporters and acquire the transcriptional, DNA methylation status, and nucleosome accessibility information from the same single cell. Fundamentally, our study will test the hypothesis that senescence is not one functional state, but instead is a composite of multiple functional units. Furthermore, we aim to prove that different tissue and pathophysiological contexts are associated with the emergence of unique senescent sub-populations, with functionalities that reflect the biological context. In addition to the cutting-edge single cell multi-omic approaches and novel tools developed by collaborators, we have also ensured this is a community-driven project by forming an advisory board composed of prominent members of the senescence and ageing communities.
Planned Impact
We live in an ageing society, however while average lifespans have increased the average health-span for an individual has not kept apace. As such age-associated disorders and pathologies are becoming an increasing fiscal and social burden on our society. Senescence represents a cellular state that is a key component of organismal ageing and the development of age-associated disorders. Recent evidence in mice suggests that targeting senescence may lead to improvements in age-related disorders and promote healthy ageing. Yet the bulk of our knowledge regarding this state is based on in vitro data, and is relatively poorly understood as an in vivo phenomenon.
As such we have proposed to develop a 'Senescence Atlas' to generate data and methodologies that will have instant impact across a wide-range of research areas and diseases.
Academic Impact: Firstly, basic and translational researchers will benefit from these data, this is exemplified by the wide-range of scientific backgrounds, and respective research questions, that comprise the members of our scientific advisory board. Additionally, we aim to be a highly transparent working group, providing in-depth technical descriptions of senescent cell isolation and data analysis tools for the wider community. Finally, this project will benefit tremendously the post-docs, involving personal development, research-specific training, and ensuring efficient and complete dissemination of information to all stakeholders.
Economic impact: We live in an ageing society and as such the incidence of age-related diseases (for which senescent cells are functionally implicated) are increasing. This has produced a fertile environment wherein biotechnology and pharmaceutical companies are attempting to develop intervention strategies to treat these disorders, however our current knowledge of what to target, with regards to in vivo senescence populations, and how amenable they are to current targeting agents is relatively low. Our data can not only be used to address the former, but will specifically address the latter. As such this has the potential to act as a catalyst for these sectors.
Societal: As mentioned above, our society has an increasing burden of age-related disorders which result in a high cost to society to treat and manage. The combined impact academically and economically has the potential to provide a profound shift in society, by promoting an increased health-span, or healthy aged population.
As such we have proposed to develop a 'Senescence Atlas' to generate data and methodologies that will have instant impact across a wide-range of research areas and diseases.
Academic Impact: Firstly, basic and translational researchers will benefit from these data, this is exemplified by the wide-range of scientific backgrounds, and respective research questions, that comprise the members of our scientific advisory board. Additionally, we aim to be a highly transparent working group, providing in-depth technical descriptions of senescent cell isolation and data analysis tools for the wider community. Finally, this project will benefit tremendously the post-docs, involving personal development, research-specific training, and ensuring efficient and complete dissemination of information to all stakeholders.
Economic impact: We live in an ageing society and as such the incidence of age-related diseases (for which senescent cells are functionally implicated) are increasing. This has produced a fertile environment wherein biotechnology and pharmaceutical companies are attempting to develop intervention strategies to treat these disorders, however our current knowledge of what to target, with regards to in vivo senescence populations, and how amenable they are to current targeting agents is relatively low. Our data can not only be used to address the former, but will specifically address the latter. As such this has the potential to act as a catalyst for these sectors.
Societal: As mentioned above, our society has an increasing burden of age-related disorders which result in a high cost to society to treat and manage. The combined impact academically and economically has the potential to provide a profound shift in society, by promoting an increased health-span, or healthy aged population.
Organisations
Publications
Chondronasiou D
(2022)
Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
in Aging cell
Taubenschmid-Stowers J
(2022)
8C-like cells capture the human zygotic genome activation program in vitro.
in Cell stem cell
Von Meyenn F
(2022)
Comparative Principles of DNA Methylation Reprogramming during Human and Mouse In Vitro Primordial Germ Cell Specification.
in Developmental cell
Gill D
(2022)
Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.
in eLife
Clark SJ
(2022)
Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis.
in Genome biology
Bergmann S
(2022)
Spatial profiling of early primate gastrulation in utero.
in Nature
Abakir A
(2023)
Direct methylation sequencing.
in Nature chemical biology
Parry A
(2022)
DNMT3A binds ubiquitinated histones to regulate bivalent genes
in Nature Genetics
Vijg J
(2023)
Mitigating age-related somatic mutation burden.
in Trends in molecular medicine
Description | As explained by the other holder of this collaborative grant, Professor Masashi Narita: We have generated several single-cell gene expression profiles. Classically, gene expression profiling is performed in many cells together, i.e. we only get an average of many cells. However, every cell has its own profile and the diversity between cells can be very high. Thanks to recent technological advancements, we can profile gene expression at a single-cell level. We applied this technology to characterise 'senescent' mouse liver cells (hepatocytes). Those cells were collectively called senescence (a unique state of the persistent stress response) but it turns out that only a subset of these cells appear to be classical senescence, and many others show an intermediate state, which is very different from senescence. We think that senescence is not an on-off thing, but rather a continuous spectrum. We believe it is crucial to understand what those 'senescence-intermediates' are to correctly treat those damaged organs. |
Exploitation Route | Quoting our collaborator and co-PI, Professor Masashi Narita: Senescence-targeted therapy is not a very popular idea to alleviate age-associated disorders. However, the diversity of senescence is poorly understood. Our single-cell research will provide a proof-of-principle for the urgency of precision senescence-targeted therapy. For example, in some contexts, it might be more beneficial to kill senescence-intermediates rather than fully senescent cells. I envisage that more precise designs for screening senescence modulators will be widely considered. |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | 6th Form Conference |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Further education students present research posters which are judged by researcher staff following conversations around their work. Presentation on research and career journey was given to all students will a Q&A following |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.babraham.ac.uk/events/2022/07/sixth-form-conference-2022-healthy-ageing |
Description | Meet a Bioscientist |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Virtual research and career talk with extended Q&A |
Year(s) Of Engagement Activity | 2022 |
Description | Sawston School student work experience |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | One week work experience placement for 6th form aged student. Engaged with lab research, the wider Institute and science careers |
Year(s) Of Engagement Activity | 2022 |